CN101453982B - Two-piece, internal-channel osmotic delivery system flow modulator - Google Patents

Two-piece, internal-channel osmotic delivery system flow modulator Download PDF

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Publication number
CN101453982B
CN101453982B CN 200780018756 CN200780018756A CN101453982B CN 101453982 B CN101453982 B CN 101453982B CN 200780018756 CN200780018756 CN 200780018756 CN 200780018756 A CN200780018756 A CN 200780018756A CN 101453982 B CN101453982 B CN 101453982B
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delivery system
osmotic delivery
housing
flow
container
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CN 200780018756
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Chinese (zh)
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CN101453982A (en )
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M·A·德斯贾丁
P·C·赞莫拉
P·E·德拉瑟纳
S·D·劳滕巴赫
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精达制药公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19Cytokines; Lymphokines; Interferons
    • A61K38/21Interferons [IFN]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T137/00Fluid handling
    • Y10T137/0318Processes
    • Y10T137/0402Cleaning, repairing, or assembling
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00Metal working
    • Y10T29/49Method of mechanical manufacture
    • Y10T29/49229Prime mover or fluid pump making
    • Y10T29/49236Fluid pump or compressor making
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00Metal working
    • Y10T29/49Method of mechanical manufacture
    • Y10T29/494Fluidic or fluid actuated device making

Abstract

An osmotic delivery system flow modulator includes an outer shell constructed and arranged for positioning in an opening of a reservoir of an osmotic delivery system, an inner core inserted in the outer shell, and a fluid channel having a spiral shape defined between the outer shell and the inner core. The fluid channel is adapted for delivery of an active agent formulation from the reservoir of the osmotic delivery system.

Description

两件式内部通道渗透递送系统流动调节器 Two-piece internal passage osmotic delivery system flow modulator

[0001] 相关申请的交叉引用 CROSS [0001] REFERENCE TO RELATED APPLICATIONS

[0002] 本申请要求2006年5月30日的美国临时申请60/809,451的优先权,所述申请的内容被并入本文作为参考。 [0002] This application claims priority to US Provisional Application No. 60 / 809,451 of May 30, 2006, the contents of which are incorporated herein by reference.

[0003] 发明背景 [0003] Background of the Invention

[0004] 本发明一般地涉及用于在流体环境中持续递送活性剂的渗透递送系统。 [0004] The present invention relates generally to sustained delivery osmotically active agent delivery system in a fluid environment. 更具体地,本发明涉及用于在流体环境中从渗透递送系统递送活性剂的流动调节器。 More particularly, the present invention relates to a flow regulator for a fluid environment from the osmotic delivery system for delivering an active agent.

[0005] 图1说明了现有技术的渗透递送系统40,如Peterson等人的美国专利6,524,305 所述的。 [0005] Figure 1 illustrates the prior art osmotic delivery system 40, such as Peterson et al in U.S. Patent 6,524,305. 所述递送系统40包括容纳渗透剂47和活性剂44的壳体42。 The delivery system 40 comprises a housing accommodating the active agent and the osmotic agent 47 44 42 分离元件46在渗透剂47和活性剂44之间形成隔离物。 Spacers 46 are formed between the active agent and the osmotic agent 47 44 separating member. 半渗透性的塞48被插入到壳体42的第一开口45中。 The semipermeable plug 48 is inserted into the first opening 45 of the housing 42. 半渗透性的塞48选择性地允许流体进入壳体42的内部。 Semipermeable plug 48 selectively permits fluid to enter the interior of the housing 42. 流动调节器20被插入到壳体42 的第二开口39中。 Flow regulator 20 is inserted into the second opening 39 in the housing 42. 流动调节器20允许活性剂44离开壳体42的内部,而控制流体反扩散到壳体42的内部。 Flow regulator 20 allows the active agent 44 leaves the interior of the housing 42, and the control fluid back diffusion into the housing 42. 在渗透递送系统40被置于流体环境中时,来自壳体42外部的流体通过半渗透性塞48进入壳体42并且渗入渗透剂47,引起渗透剂47膨胀。 When the osmotic delivery system 40 is placed in a fluid environment, fluid from the outside of the housing 42 through semipermeable plugs 48 penetrate into the housing 42 and the osmotic agent 47, causing the osmotic agent 47 to swell. 渗透剂47在膨胀时使分离元件46移动,引起活性剂44通过流动调节器20递送到应用环境。 47 that the osmotic agent expands upon the separating element 46 is moved to cause delivery of the active agent 44 through the flow regulator 20 to the application environment.

[0006] 在图1中所示的现有技术的渗透递送系统40中,流动调节器20的外表面包括螺旋状的递送通路32,活性剂44通过所述递送通路32从壳体42的内部流通到外部。 [0006] In the prior art shown in FIG. 1 osmotic delivery systems 40, 32, 44 through the delivery agent inside the outer surface of the flow regulator 20 includes a helical delivery path 32 from the passage 42 of the housing circulation to the outside. 形成螺旋状递送通路32的螺纹(thread) 36抵接壳体42的内表面43,使得活性剂44在通过螺旋状递送通路32时接触壳体42的内表面43。 A helical thread delivery passage (Thread) 36 against the inner surface 32 of the contact housing 42 43, 44 43 such that the active agent in contact with the inner surface of the housing 32 through the helical delivery path 42. 对螺旋状递送通路32的间距、距离、横截面积、和形状进行选择,使得从流体环境到壳体42中的反扩散最小化。 The pitch of the helical delivery path 32, from the cross-sectional area, and shape are chosen such that fluid from the environment to the housing 42 in the inverse diffusion is minimized. 在流动调节器20中提供填充孔22和排气孔24。 Providing fill hole 22 and vent hole 24 in the flow regulator 20. 在装配这种渗透递送系统40时,首先将流动调节器20插入到壳体42中。 40, the first flow regulator 20 is inserted into the housing assembly 42 in such a delivery system penetration. 然后通过填充孔22将活性剂44注射到壳体42中,而壳体42中的气体通过排气孔M流出。 The active agent 22 is then injected through the filling hole 44 into the housing 42 and the housing 42 the gas flows through the vent holes M. 其后,将端盖沈插入到孔22、24中,使得只通过螺旋状递送通路32发生活性剂44的递送。 Thereafter, the end caps 22, 24 sink into the hole, such that only the helical delivery path 32 through the delivery of the active agent 44 occurs.

[0007] 从上述内容可见,仍希望在渗透递送系统中提供另外的可靠性和流动调节能力。 [0007] apparent from the above, is still desirable to provide additional reliability and flow modulator capabilities in osmotic delivery systems. 发明内容 SUMMARY

[0008] 在一个方面中,本发明涉及渗透递送系统流动调节器,其包括被构造和布置用于定位在渗透递送系统的容器开口中的外壳,插入到外壳中的内芯,和在所述外壳和内芯之间限定的螺旋状流动通道,所述流动通道适合用于从渗透递送系统的容器递送活性剂制剂。 [0008] In one aspect, the present invention relates to osmotic delivery system flow modulator which comprises a housing constructed and arranged for positioning the container opening in the osmotic delivery system is inserted into the core housing, and in the defined between the outer shell and the inner core of the helical flow passage, the flow passage from a container suitable for use in osmotic delivery system to deliver the active agent formulation.

[0009] 在另一个方面中,本发明涉及渗透递送系统,其包括容器;设置在所述容器的第一末端、用于选择性地允许进入容器的流动的半渗透性塞;设置在所述容器的第二末端的流动调节器,所述流动调节器包括适合用于将包含在容器中的活性剂制剂递送到所述渗透递送系统在其中起作用的流体环境中的内部螺旋通道。 [0009] In another aspect, the present invention relates to osmotic delivery system, comprising a container; disposed at a first end of the container, for selectively allowing flow into the container of the semipermeable plug; provided the the second end of the container flow regulator, the flow regulator comprises a container suitable for containing the active agent formulation is delivered to the osmotic delivery system in a fluid environment in which the function of an internal spiral channel.

[0010] 在又一个方面中,本发明涉及用于活性剂制剂的可植入的递送系统,其包括由非渗透性材料制成的容器,在所述容器中的包含渗透动力物质的第一室,在所述容器中的包含活性剂制剂的第二室,设置在容器的第一末端与第一室邻接的半渗透性塞,和设置在容器的第二室与第二室邻接的如上所述的流动调节器。 [0010] In yet another aspect, the present invention relates to implantable active agent formulation delivery system, comprising a container made of non-permeable material, a first container containing the osmotic engine of chamber, the second chamber of the container containing the active agent formulation, a second container disposed in a second chamber adjacent to the chamber and a first end of the first chamber of the container adjacent the semipermeable plug disposed above and said flow regulator.

[0011] 从以下的说明书和随后的权利要求显而易见本发明的其它特征和优点。 [0011] Other features and advantages become apparent from the following disclosure of the present specification and claims. 附图说明 BRIEF DESCRIPTION

[0012] 如下所述的附图说明本发明的典型的实施方案,并且不应将其考虑为限制本发明的范围,因为本发明可以允许其它同样有效的实施方案。 [0012] The following description of the drawings exemplary embodiments of the present invention, and should not be considered as limiting the scope of the present invention, as the invention may admit to other equally effective embodiments. 附图中不一定是按比例的,并且为了清楚和简明,图中的某些特征和某些视图可能在比例上或示意性地放大。 The drawings are not necessarily to scale, for clarity and conciseness, certain features and certain views of the figures may be exaggerated or schematically in scale.

[0013] 图1描述现有技术渗透递送系统的剖视图。 Cross-sectional view of the delivery system [0013] FIG 1 depicts a prior art penetration.

[0014] 图2A描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和形成在内芯中的内部螺旋流动通道。 [0014] FIG 2A is described a sectional view of a portion of the flow regulator, said flow regulator having an inner core inserted in the housing formed in the inner core and the inner helical flow channel.

[0015] 图2B描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和形成在外壳中的内部螺旋流动通道。 [0015] Figure 2B a cross-sectional view of a portion of the described flow regulator, said flow regulator having a housing inserted in the inner core and is formed in the housing inner helical flow channel.

[0016] 图2C描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和形成在内芯和外壳中的内部螺旋流动通道。 [0016] Figure 2C a cross-sectional view of a portion of the described flow regulator, said flow regulator having a housing inserted in the inner core and the inner core and the outer shell is formed in the inner helical flow channel.

[0017] 图2D描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和流动嵌入物,所述流动嵌入物包括插入在内芯和外壳之间的内部螺旋流动通道。 [0017] FIG. 2D cross-sectional view of a portion of the described flow regulator, said flow regulator having a housing inserted in the inner core and the flow insert, said insert comprising a flow insert including an internal spiral flow passage between the core and the shell .

[0018] 图2E描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和内芯和外壳上的接合面,用于防止内芯从外壳排出。 A cross-sectional view of a portion [0018] FIG. 2E describes a flow regulator, the flow regulator is inserted in the housing having an inner core and an inner core and an engagement surface on the housing, for preventing the inner core from the housing is discharged.

[0019] 图3描述具有图2A的流动调节器的渗透递送系统的剖视图。 [0019] Figure 3 depicts a cross-sectional view of an osmotic delivery system flow modulator of FIG. 2A having.

[0020] 图4描述使用图3的渗透递送系统得到的活性剂的体外累计释放。 [0020] FIG. 3 FIG. 4 describes the use of osmotic delivery of the active agent system obtained in vitro cumulative release.

[0021] 发明详述 [0021] DETAILED DESCRIPTION

[0022] 现在参考如附图中说明的几个优选实施方案详细描写本发明。 [0022] Now with reference to several preferred embodiments illustrated in the accompanying drawings as detailed description of the present invention. 在描述优选实施方案时,阐述了许多细节以便提供对本发明的充分理解。 In describing the preferred embodiments, numerous details are set forth in order to provide a thorough understanding of the present invention. 然而,本领域技术人员可以在不使用一些或全部这些细节的情况下实践本发明。 However, those skilled in the art may be practiced without using some or all of these details or the present invention. 在其它情况中,对公知的特征和/或工艺步骤没有进行详细描述,以便不必要地使本发明不清楚。 In other instances, well-known features and / or process steps have not been described in detail as not to unnecessarily obscure the present invention. 另外,相似的或相同的参考数字用于表示共用的或类似的元件。 Further, similar or identical reference numerals are used to denote common or analogous elements.

[0023] 图2A到2E描述用于从渗透递送系统的容器递送活性剂制剂的流动调节器200的部分剖视图。 [0023] FIGS. 2A to 2E describes a container from the osmotic delivery system 200 is a partial sectional view of a delivery flow regulator active agent formulation. 参考图2A,流动调节器200具有暴露于渗透递送系统的容器中的活性剂制剂的入口侧201,和暴露于渗透递送系统在其中起作用的流体环境的出口侧203。 2A, the flow modulator 200 has an inlet side 201 of the active agent formulation is exposed to an osmotic delivery system containers and exposed to the osmotic delivery system in the fluid environment in which the outlet side function 203. 典型地,流体环境是液相环境,也就是说,所述流体包含水。 Typically, the fluid environment is an aqueous environment, i.e., the fluid comprises water. 流动调节器200包括外壳202和插入到外壳202中并且通常为圆柱形的内芯204。 A flow regulator 200 comprising a housing 202 and inserted into the housing 202 and generally cylindrical inner core 204. 在外壳202和内芯204之间有螺旋状的流动通道206从流动调节器200的入口侧延伸到出口侧203。 Between the housing 202 and the inner core 204 having a helical flow passage 206 extending from the inlet side of the flow regulator 200 to the outlet 203 side. 流动通道206的所有或显著的部分可为螺旋状。 All or a significant portion of the flow channel 206 may be helical. 流动通道206在流动调节器200内部。 206 in the flow modulator 200 inside the flow passage. 因此,流动调节器200在通过流动通道206的活性剂制剂和渗透递送系统的容器之间形成屏障。 Thus, the flow regulator 200 forms a barrier between the delivery system and penetrate through the active agent formulation flow passage 206 of the container.

[0024] 在图2A-2C中,内芯204的外表面210与外壳202的内表面212配合。 [0024] In Figures 2A-2C, the outer surface of the inner core 204 and the inner surface 210 of the housing 202 of the mating 212. 流动通道206可以形成在内芯204的外表面210中,如图2A所示,或者流动通道206形成在外壳202 的内表面212中,如图2B所示。 The flow passage 206 may be formed in the outer surface 204 of the inner core 210, as shown in FIG. 2A or flow passage 206 formed in the inner surface 212 of the housing 202, shown in Figure 2B. 或者,如图2C所示,流体通道206可以包括形成在内芯204 的外表面210中的第一流动通道206a和形成在外壳202的内表面212中的第二流动通道206b,其中第一流动通道206a和第二流动通道206b彼此抵接或连通。 Alternatively, shown in Figure 2C, the fluid channel 206 may include an outer surface of the inner core 204 form a first flow passage 210 and 206a formed on the inner surface 212 of the housing 202 in the second flow path 206b, wherein the first flow channel 206a and the second flow passage 206b communicate with each other or abut. 每个流动通道206a、 206b的所有或显著的部分为螺旋状。 Each flow channel 206a, 206b, all or a significant portion of helical shape. 或者,如图2D所示,流动嵌入物214可以布置在内芯204的外表面210和外壳202的内表面212之间,其中流动嵌入物214提供流动通道206。 Alternatively, as shown in FIG. 2D, a flow insert 214 may be disposed between the outer surface 212 of the inner core 204 and the inner surface 210 of the housing 202, wherein the flow insert 214 provides the fluid channel 206. 流动嵌入物214可为例如盘管,管的各个匝之间的距离起到流动通道206的作用。 Flow insert 214 may act as a flow channel 206 is the distance between the individual turns of the coil, for example, tubes. 或者, 流动嵌入物214可为其中形成有螺旋凹槽的中空的圆柱体或套管,其中螺旋凹槽起到流动通道206的作用。 Alternatively, the flow insert 214 may be formed with a spiral groove or a hollow cylinder in which the sleeve, wherein the spiral groove 206 functions as a flow passage. 流动通道206可具有任何所需的横截面,其实例包括环形或D形。 The flow channel 206 may have any desired cross-section, examples of which include circular or D-shaped. 在图2A-2E中表示了D形的流动通道。 It represents a D-shaped flow path in FIG. 2A-2E. 流动通道206的长度取决于渗透递送系统的结构和所需的释放速率。 Length of the flow channel 206 depends on the structure and the desired release rate of the osmotic delivery system. 典型地,(流动通道206的(螺旋)长度为10到50mm。典型地,流动通道206 的有效截面直径为0. 1到0.5mm。这些范围作为实例给出,而不是用于限制本发明,除非另有说明。 Typically, (a flow path (spiral) length of 10 to 206 is 50mm. Typically, the effective cross-sectional diameter of the flow passage 206 is 0.1 to 0.5mm. These ranges are given as examples, and not intended to limit the present invention, Unless otherwise indicated.

[0025] 参考图2A-2D,对内芯204的最大外径和外壳202的最大内径进行选择,使得在内芯204的外表面210与外壳202的内表面212之间形成过盈配合或密封。 [0025] with reference to FIGS. 2A-2D, the largest outer diameter and a maximum inner diameter of inner core 204 of the housing 202 are selected such that the outer surface 210 of inner core 204 is formed an interference between the inner surface 202 of the housing 212 of the mating seal or . 这种过盈配合或密封限制制剂流到通道206中。 This interference fit or seal the flow passage 206 to limit the formulation. 这种过盈配合或密封足以防止内芯204和/或流动嵌入物214从外壳202排出。 This interference fit or seal sufficient to prevent the inner core 204 and / or flow insert 202 214 is discharged from the housing. 另一方面,在图2A-2C中,内芯204和外壳202的表面210、212的配合部分分别可包括例如螺纹连接、粘合连接、焊接连接等特征,以便另外相对于外壳202固定内芯204。 On the other hand, in FIGS. 2A-2C, with the portion of the inner core 204 and the surfaces 210, 212 of the housing 202, respectively, may comprise a threaded connection, adhesive connection, welded connection, etc. For example, features additional to the inner core 202 is fixed relative to the housing 204. 在图2D中,可以在分别与内芯204和外壳202的表面210、212配合的流动嵌入物214的内和外表面2Ha、214b的部分之间形成类似的连接特征。 In FIG. 2D, 2Ha, similar connection features formed portion 214b may be embedded between the inner and outer surfaces 214 of the core 204, respectively, and the inner surface 202 of the housing 210, 212 with the flow. 图2E公开了用于防止内芯204从外壳202排出的备选方法,其包括在内芯204的外表面210上的外侧肩部216, 其与外壳202的内表面212上的内侧肩部218抵接/啮合。 FIG. 2E discloses an alternative method for the inner core 204 from the housing 202 to prevent discharge, which includes an outer shoulder on an outer surface of the inner core 204 210 216, a shoulder 218 on the inner side of the inner surface 212 of the housing 202 abutting / engaged. 这样防止了内芯204通过流动调节器200的出口侧203排出。 This prevents the discharge outlet of the core 204,203 side by a flow regulator 200. 肩部216、218的抵接/啮合表面可为平的或可为逐渐缩减的,如图2E中所示。 216, 218 abutting the shoulder / engaging surfaces may be flat or may be tapered as shown in FIG. 2E.

[0026] 使用抵接/啮合肩部216、218防止内芯204从外壳202排出到渗透递送系统在其中起作用的流体环境中可以适用于图2A-2D中所示的任一实施例中。 [0026] The use of abutting / engaging shoulders 216, 218 prevent the inner core 204 is discharged from the housing 202 to the osmotic delivery system in which any function can be applied to a fluid environment shown in Figures 2A-2D an embodiment. 此外,可以将图2A-2E 中所示实施例的任何特征互换和组合,以产生流动调节器200的替代实施例。 Further, any of the features may be interchanged and combinations of the embodiments shown in FIGS. 2A-2E, to produce a flow regulator 200 in alternative embodiments. 例如,在图2E 中,螺旋状的通道也可以如图2C中所示位于外壳202的内表面212中。 For example, in FIG. 2E, the helical channel may be located within the surface of the housing 202 as shown in FIG. 2C, 212. 或者,在图2D中, 螺旋状的通道也可以位于外壳202的内表面212中和/或内芯204的外表面210中,分别如图2A和2B中所述,其中外壳202和/或内芯204中的通道与流动嵌入物214中的流动通道206邻接或连通。 Alternatively, in 2D, the helical channel may be on the inner surface 202 of the housing 212 and / or the outer surface 210 of the core 204, respectively, in the Figures 2A and 2B, there is the housing 202 and / or the the core 204 insert 206 adjacent to the flow passage 214 in the flow channels or communication.

[0027] 参考图2A-2E,外壳202、内芯204、和流动嵌入物214优选由惰性和生物相容的材料形成。 [0027] Referring to FIG 2A-2E, the housing 202, the inner core 204, and the flow insert 214 is preferably formed from an inert and biocompatible material. 惰性的生物相容的材料的实例包括但不限于非反应性聚合物和金属例如钛、不锈钢、钼和它们的合金、和钴铬合金。 Examples of inert, biocompatible materials include, but are not limited to non-reactive polymers and metals such as titanium, stainless steel, molybdenum and their alloys, and cobalt-chromium alloys. 非反应性聚合物可用于其中希望在将活性剂制剂递送到渗透递送系统在其中起作用的流体环境中时避免活性剂制剂和金属材料之间的相互作用的情况。 A non-reactive polymer which may be used in the desired active agent formulation is delivered to the osmotic delivery system which avoid interaction between the active agent formulation and a metallic material acting upon a fluid environment. 适合的非反应性聚合物的实例包括但不限于聚芳醚酮例如聚醚醚酮和聚芳醚醚酮、超高分子量聚乙烯、氟化的乙烯-丙烯、聚甲基戊烯、和液晶聚合物。 Examples of suitable non-reactive polymers include, but are not limited to, poly aryl ether ketone and polyether ether ketone e.g. polyaryl ether ether ketone, ultra high molecular weight polyethylene, fluorinated ethylene - propylene, polymethylpentene, and liquid crystal polymer. 优选地,至少以下表面由不会对活性剂制剂具有有害作用的材料制成或者涂有所述材料,所述表面包括在活性剂制剂流过流动通道206时暴露于活性剂制剂的外壳202、内芯204、和流动嵌入物214 的表面。 Preferably, at least the surfaces have deleterious effects on the active agent from the formulation is not made of a material or coated with said material, said surface comprising active agent formulation flows through the flow passage 206 of the housing upon exposure to active agent formulation 202, inner core 204, and a flow surface 214 of the insert. 在优选的实施例中,上述表面由惰性的和生物相容的非金属材料制成。 In a preferred embodiment, it said surface made of an inert and biocompatible non-metallic materials. 这种非金属材料可以是非反应性聚合物,其实例在上述给出。 Such non-metallic material may be a non-reactive polymer, examples of which are given above.

[0028] 可以对流动通道206的长度、横截面形状、和流通区域进行选择,使得活性剂制剂通过流动通道206的平均线速度比物质由于扩散或渗透从渗透递送系统在其中起作用的流体环境线性向内流入的平均线速度更高。 [0028] The length of the flow channel 206 can the cross-sectional shape, and the flow area selected, active agent formulation such that the average linear velocity through the flow passage 206 than the material from the permeate by diffusion or osmotic delivery system in which the fluid environment acts the higher the average linear velocity of the linear inward flows. 这样可具有衰减或缓和反扩散的作用,所述如果不对反扩散进行控制,则可能污染渗透递送系统中的活性剂制剂。 This has the effect of attenuating or alleviating back diffusion, the anti-diffusion if not controlled, could contaminate the active agent formulation in the osmotic delivery system. 可以通过调节流动通道206的几何形状来调节活性剂制剂的释放速度,如以下所述。 Release rate can be adjusted by adjusting the active agent formulation flow passage 206 geometry, as described below.

[0029] 活性剂通过流动通道206的对流流动由渗透递送系统的泵送速率和渗透递送系统的容器中的活性剂制剂中的活性剂浓度决定。 Pumping rate [0029] The convective flow of active agent through the fluid channel 206 by the osmotic delivery system and the concentration of the active agent formulation in the osmotic delivery system in the vessel is determined. 对流流动可以表示为: Convective flow may be expressed as:

[0030] [0030]

Figure CN101453982BD00061

[0031] 其中Qca是表示为mg/天的活性剂(beneficial)的对流转运,Q是表示为cm3/天的活性剂制剂的总体对流转运,和Ca是表示为mg/cm3的渗透递送系统的容器内的活性剂制剂中活性剂的浓度。 [0031] where Qca is a convective transport mg / day of active agent (Beneficial) is, Q is expressed as the overall convective transport of the active agent formulation cm3 / day, and Ca is delivered to the permeate mg / cm3 of the system concentration of the active agent in the active agent formulation within the container.

[0032] 活性剂离开流动通道206的扩散流动是活性剂浓度和扩散率以及流动通道206的横截面形状和长度的函数。 [0032] The diffusion of the active agent flow away from the flow channel 206 is a function of the cross-sectional shape and length of the active agent concentration and diffusivity and the flow passage 206. 扩散流动可以表示为: Diffusion flow may be expressed as:

[0033] [0033]

Figure CN101453982BD00062

[0034] 其中Qda是表示为mg/天的活性剂的扩散转运,D是表示为cm2/天的通过流动通道206的扩散率,r是表示为cm的流动通道206的有效内径,Δ Ca是表示为mg/cm3的渗透递送系统容器内的活性剂制剂的活性剂浓度与流动调节器200的递送孔205外侧的流体环境中的活性剂浓度之差,而L是表示为cm的流动通道206的(螺旋)长度。 [0034] where Qda is a diffusion transport of the active agent mg ​​/ day, D is the diffusion rate cm2 / day through the flow channel 206, r is expressed effective internal diameter in cm of the flow channel 206, Δ Ca is denotes delivery of an active agent concentration and flow conditioner active agent formulation within the system vessel osmotic mg / cm3 difference surfactant concentration of the fluid environment 205 outside the delivery hole 200, and L is expressed in cm of the flow channel 206 the (spiral) length.

[0035] 通常,渗透递送系统内活性剂制剂中的活性剂浓度比应用的流体环境中的活性剂浓度大得多,使得所述差ACa可接近渗透递送系统中活性剂制剂内的活性剂浓度Ca。 [0035] In general, osmotic delivery fluid environment surfactant concentration much greater concentration of active agent in the active agent formulation within the system than the application, so that the difference ACa accessible osmotic delivery of the active agent concentration in the system in active agent formulation Ca. 因此: therefore:

[0036] [0036]

Figure CN101453982BD00063

[0037] 通常期望保持活性剂的扩散通量比活性剂的对流流动小得多。 [0037] The convective flow is generally desirable to maintain the active agent much less than the diffusion of the active agent through. 这可以表示如下: This can be expressed as follows:

Figure CN101453982BD00064

[0038] — =-。 [0038] - = -. 一=-<1 A = - <1

[0039] 方程(4)表示相对扩散通量随体积流速和通路长度的增加而降低,随扩散率和通道半径的增加而增加,并且与活性剂浓度无关。 [0039] Equation (4) represents the relative diffusive flux with increasing volumetric flow rate and path length decreases with increasing diffusivity and channel radius increases, and is independent of active agent concentration.

[0040] 其中流动通道206在渗透递送系统中开口处的水的扩散通量可以近似表示如下: [0040] wherein the flow channel 206 in the opening osmotic delivery system diffusive flux of water may be approximated as follows:

[0041] [0041]

Figure CN101453982BD00065

(5) (5)

[0042] 其中Co是表示为mg/cm3的水的浓度分布,Q是表示为mg/天的质量流速,L是表示为cm的流动通道206的长度,Dw是表示为cm2/天的水通过流动通道206中物质的扩散率,和A是表示为cm2的流动通道206的横截面积。 [0042] where Co is the concentration of water in mg / cm3 distribution, Q is mass flow rate of mg / day, L is the length in cm of the flow channel 206, Dw is expressed as cm2 / day water by diffusivity substance in the flow channel 206, and a is a cross-sectional area of ​​the flow channel 206 cm2.

[0043] 跨越递送孔的流体动力压降可以计算如下: [0043] The hydrodynamic pressure drop across the delivery orifice can be calculated as follows:

[0044] [0044]

Figure CN101453982BD00066

[0045] 其中Q是表示为mg/天的质量流速,L是表示为cm的螺旋流动通道长度,μ是制剂的粘度,r是表示为cm的流动通道的有效内径。 [0045] where Q is the mass flow rate is expressed as mg / day, L is expressed in cm spiral flow channel length, μ is the viscosity of the formulation, r is expressed as the effective inner diameter of the flow passage cm.

[0046] 图3表示包括流动调节器200的渗透递送系统300。 [0046] FIG. 3 shows a flow regulator 200 comprising osmotic delivery system 300. 尽管渗透递送系统300表示为具有图2A的流动调节器200,显而易见,可以将图2A-2E中所示的任何流动调节器200用于渗透递送系统300。 Although the osmotic delivery system 300 of FIG. 2A is represented as having a flow regulator 200, apparent, it may be any flow regulator shown in FIGS. 2A-2E for osmotic delivery systems 200, 300. 渗透递送系统300包括容器302,其大小可为使得可以将其植入在体内。 Osmotic delivery system 300 includes a container 302, which may be sized such that it can be implanted in vivo. 容器302具有开口末端304、306。 Container 302 having an open end 304, 306. 流动调节器200被插入到开口末端304中。 Flow modulator 200 is inserted into the opening 304 in the tip. 半渗透性塞308被插入到开口末端306中。 Semipermeable plug 308 is inserted into the opening 306 in the tip.

[0047] 半渗透性塞308是控制来自渗透递送系统在其中起作用的流体环境的流体流动到容器302中的膜。 [0047] The semipermeable plug 308 is a control fluid from the osmotic delivery system in the fluid environment in which the function to flow into the container 302 in the film. 半渗透性塞308允许来自流体环境的流体进入容器302。 Semipermeable plug 308 allows fluid from the fluid container 302 into the environment. 由于半渗透性塞308的半渗透性性质,使容器302中的组合物被阻止通过半渗透性塞308流出容器302。 Since semipermeable nature of the semipermeable plug 308, the composition of the container 302 is prevented by the semipermeable plug 308 out of the container 302. 半渗透性塞308可以部分或完全被插入到开口末端306中。 Semipermeable plug 308 may be partially or fully inserted into the opening 306 in the tip. 在前一种情况中,半渗透性塞308可包括扩大的末端部分308a,其作为与容器302的末端啮合的止动元件起作用。 In the former case, the semipermeable plug 308 may include an enlarged end portion 308a, which functions as a stop member engaged with the ends of the container 302. 半渗透性塞308的外表面308b可具有与容器302的内表面310啮合的突起或凸纹308c,从而将半渗透性塞308锁定在容器302上并且允许在容器302和半渗透性塞308之间形成密封。 The outer surface of the semipermeable plug 308 may have protrusions 308b or 308c and the inner surface of the ridges 310 of container 302 engage, thereby locking the semipermeable plug 308 allows the container 302 and container 302 in the plug 308 and the semipermeable formed between the seal. 容器302还可以包括底切,用于接受半渗透性塞308上的突起308c。 Container 302 may further include an undercut for receiving the semipermeable plug 308 on the projection 308c. 用于半渗透性塞308的半渗透性材料是可以在润湿时符合容器302的形状并且可以粘附容器302的内表面310的材料。 A semipermeable plug of semipermeable material 308 can conform to the shape of the container 302 when wet and can be adhered to the inner surface of the container material 302 310. 典型地,这些材料是聚合物材料,其可以根据泵送速率和系统配置要求进行选择。 Typically, these materials are polymeric materials, which can be selected according to the configuration requirements of the system and the pumping speed. 适合的半渗透性材料的实例包括但不限于增塑的纤维素材料、增强的聚甲基丙烯酸甲酯(PMMA)例如羟乙基甲基丙烯酸酯(HEMA)、和弹性体材料例如聚氨酯和聚酰胺、聚醚-聚酰胺共聚物、热塑塑料共聚多酯等等。 Examples of suitable semipermeable materials include, but are not limited to plasticized cellulosic materials, enhanced polymethyl methacrylate (PMMA) such as hydroxyethyl methacrylate (HEMA), and elastomeric materials such as polyurethane and polyethylene amides, polyether - polyamide copolymers, thermoplastic copolyesters and the like. 通常优选聚氨酯。 Polyurethane is generally preferred.

[0048] 在容器302中限定两个室312、314。 [0048] define two chambers 312, 314 in the container 302. 室312、314由隔离物316例如滑动的活塞或柔性膜片分隔,所述隔离物配置为在容器302内配合和产生密封接触,和用于在容器302内纵向地移动或变形。 Chambers 312, 314 such as a sliding piston or flexible diaphragm 316 separated by a spacer, the spacer is configured to fit and sealing contact to occur within the container 302 within the container 302 and a longitudinally moved or deformed. 优选地,隔离物316由非渗透性的弹性材料形成。 Preferably, the spacer 316 is formed of a non-permeable elastomeric material. 例如,隔离物316可为由非渗透性弹性材料制成的滑动活塞并且可以包括与容器302的内表面310形成密封的环形突起316a。 For example, the spacer 316 may be a slidable piston made of an impermeable resilient material and may include an annular inner surface 310 of the container 302 forms a seal projection 316a. 渗透动力物质318设置在与半渗透性塞308邻接的室314中,活性剂制剂设置在与流动调节器200邻接的室312中。 Osmotic engine 318 is provided with a semipermeable plug 308 adjacent to the chamber 314, the active agent formulation 312 is provided in the flow regulator 200 adjacent chamber. 隔离物316使活性剂制剂320与被允许通过半渗透性塞308进入容器302的环境流体分隔,使得在使用中,在稳态流动时,活性剂制剂320 以与流体从流体环境通过半渗透性塞308流入容器302的速率相当的速率被排出通过流动通道206。 Spacer 316 so that the active agent formulation 320 is allowed to pass through the semipermeable plug 308 into the container 302 separated by an environmental fluid, such that, in use, during steady state flow, active agent formulation 320 and fluid from the fluid environment through the semipermeable rate of plug 308 into the container 302 is discharged at a rate equivalent to 206 through the flow channel.

[0049] 渗透动力物质318可为如所示的片剂形式。 [0049] The osmotic engine 318 may be in the form of tablets as shown. 可以使用一种或多种这种片剂。 Possible to use one or more of such tablets. 或者, 渗透动力物质318可具有其它形状、质地、密度、和稠度。 Alternatively, the osmotic engine 318 may have other shape, texture, density, and consistency. 例如,渗透动力物质318可为粉末或颗粒形式。 For example, the osmotic engine 318 may be in powder or particulate form. 渗透动力物质318可包括渗透聚合物(osmopolymer)。 Osmotic engine 318 may comprise osmopolymer (osmopolymer). 渗透聚合物是可以吸收含水流体例如水和生物学流体并且在吸入含水流体时膨胀或扩张到平衡状态并且保留显著部分被吸收流体的亲水聚合物。 The osmopolymers can absorb aqueous fluids such as water and biological fluids and swell or expand to an equilibrium state and retain a significant portion of the hydrophilic polymer in the fluid is absorbed an aqueous fluid intake. 渗透聚合物膨胀或扩张到非常高的程度,通常表现为2 到50倍体积增加。 The osmopolymers swell or expand to a very high degree, usually presents increased 2-50 fold volume. 渗透聚合物可以是或不是交联的。 The osmopolymers can be crosslinked or not. 优选的渗透聚合物是轻微交联的亲水聚合物,这种交联是由共价键或离子键或膨胀之后的残留结晶区形成的。 Preferred osmopolymers are lightly crosslinked hydrophilic polymers, such crosslinking is formed by covalent bonds or ionic bonds or residue crystalline regions after swelling. 渗透聚合物可以是植物、动物、或合成来源的。 The osmopolymers can be plant, animal, or synthetic origin. 适合用于渗透动力物质318的渗透聚合物或亲水聚合物的实例包括但不限于分子量为30,000到5,000,000的聚(羟基烷基甲基丙烯酸酯);分子量为10,000到360,000的聚乙烯吡咯烷酮(PVP);阴离子型和阳离子型水凝胶;聚电解质复合物;低乙酸根残留、用乙二醛、甲醛、或戊二醛交联并且聚合度为200到30,000的聚乙烯醇, 甲基纤维素、交联的琼脂和羧甲基纤维素的混合物;羟丙基甲基纤维素和羧甲基纤维素钠的混合物;羟丙基乙基纤维素和羧甲基纤维素钠盐的混合物;羧甲基纤维素钠;羧甲基纤维素钾盐;由马来酸酐与苯乙烯、乙烯、丙烯、丁烯、或异丁烯的细分散共聚物的分散体形成的不溶于水的、水可膨胀的共聚物,每种共聚物的每摩尔马来酸酐具有0. 001到约0. 5摩尔的饱和交联剂;N-乙烯基内酰胺的水可膨胀的聚合物;聚氧化乙烯-聚氧化丙烯凝胶 Examples suitable for use in the osmotic engine osmopolymers or hydrophilic polymers include, but are not limited to 318 molecular weight poly (hydroxy alkyl methacrylate) of 30,000 to 5,000,000; molecular weight of 10,000 to polyvinylpyrrolidone (PVP) 360,000; the anionic and cationic hydrogels; polyelectrolyte complexes; low acetate residual, with glyoxal, formaldehyde, or glutaraldehyde and a degree of polymerization of 200 to 30,000 polyvinyl alcohol, methyl cellulose, crosslinked agar and carboxymethyl cellulose; hydroxypropylmethyl cellulose and a mixture of sodium carboxymethyl cellulose; hydroxypropyl ethylcellulose and a mixture of carboxymethyl cellulose sodium salt; sodium carboxymethyl cellulose; carboxymethyl cellulose potassium salt; manufactured by finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene, isobutylene or dispersion water-insoluble, water-swellable copolymer formed per each mole of maleic anhydride copolymers with unsaturated crosslinker 0.001 to about 0.5 moles; N- vinyl lactam water expanded polymer; polyoxyethylene - polyoxypropylene gels ;聚氧化丁烯-聚乙烯嵌段共聚物凝胶;角豆树胶;聚丙烯酸凝胶;聚酯凝胶;聚脲凝胶;聚醚凝胶;聚酰胺凝胶;聚纤维素凝胶;聚树胶凝胶(polygumgel);吸收和吸附渗透玻璃状水凝胶并且降低其玻璃化温度的水的最初干燥的水凝胶。 ; Polybutylene oxide - polyethylene block copolymer gels; carob gum; polyacrylic acid gel; polyester gel; polyurea gel; polyether gel; polyacrylamide gel; poly cellulose gel; poly gum gel (polygumgel); osmotic absorption and adsorption glassy hydrogel and lowers its glass transition temperature of the water initially dried hydrogel. 渗透聚合物的其它实例包括形成水凝胶的聚合物,例如:CARB0P0L ®,酸性的羧基聚合物,一种丙烯酸的聚合物并且用聚烯丙基蔗糖交联的,又名聚丙烯酸和聚羧乙烯,分子量为250,000到4,000, 000 ;CYNAMER®聚丙烯酰胺;交联的水可膨胀的茚-马来酸酐聚合物;分子量为80,000到200,000的G00D-RITE® 聚丙烯酸;分子量为100,000到5,000,000和更高分子量的POLYOX ®聚环氧乙烷聚合物; 淀粉接枝共聚物;由缩合的葡萄糖单元组成的AQUA KEEPS®丙烯酸酯聚合物多糖,例如二酯交联的聚糖(polygluran);等等。 Other examples of osmopolymers include polymers forming the hydrogel, for example: CARB0P0L ®, acidic carboxy polymers, a polymer of acrylic acid and polyallyl sucrose with crosslinked, polyacrylic acid and carbopol also known as ethylene, a molecular weight of 250,000 to 4,000, 000; CYNAMER® polyacrylamides; cross-linked water-swellable indene - maleic anhydride polymer; molecular weight of 80,000 to 200,000 polyethylene G00D-RITE® acrylic acid; molecular weight of 100,000 to 5,000,000 and higher molecular weight polyethylene oxide is POLYOX ® polymers; starch graft copolymers; condensed glucose units of the polysaccharide acrylate polymer AQUA KEEPS®, for example, cross-linked glycan diester (polygluran); and the like. 除了渗透聚合物之外或代替渗透聚合物,渗透动力物质318还可以包括渗透剂(osmagent)。 In addition to or instead of osmopolymer osmopolymer, the osmotic engine 318 may also include a penetrant (osmagent). 渗透剂包括相对于外部流体表现出跨半渗透性壁的渗透压梯度的无机和有机化合物。 With respect to an external fluid penetrants include inorganic and organic compounds exhibit an osmotic pressure gradient across the semipermeable wall. 渗透剂吸收流体到渗透系统中,从而利用流体推动制剂,用于递送通过流动调节器。 Penetrant absorbing fluid into the osmotic system, thereby promoting the use of a fluid formulation for delivery through the flow modulator. 渗透剂又名渗透活性化合物或溶质。 Also known as osmotically active compounds or penetrant solutes. 可用于渗透动力物质318的渗透剂的实例包括硫酸镁、氯化镁、氯化钠、硫酸钾、硫酸钠、硫酸锂、磷酸氢钾、甘露醇、尿素、肌醇、琥珀酸镁、酒石酸、碳水化合物例如棉籽糖(raffmose)、蔗糖、葡萄糖、乳糖、 山梨醇及其混合物。 Examples of the penetrant used osmotic engine 318 include magnesium sulfate, magnesium chloride, sodium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium hydrogen phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates e.g. raffinose (raffmose), sucrose, glucose, lactose, sorbitol and mixtures thereof.

[0050] 活性剂制剂320可包括一种或多种活性剂.活性剂可为任何生理学或药理学活性的物质,特别是已知用于递送给人体或动物体的那些,例如药物、维生素、营养素等。 [0050] The active agent formulation 320 may include one or more active agents. The active agent may be any physiologically or pharmacologically active substances, in particular known for delivery to a human or animal body are those, such as drugs, vitamins, and other nutrients. 可通过流动调节器200用渗透递送系统300递送的活性剂包括但不限于作用于传染病、慢性疼痛、 糖尿病、外周神经、肾上腺素能受体、胆碱能受体、骨骼肌、心血管系统、平滑肌、血液循环系统、突触位置、神经效应器接合位置、内分泌和激素系统、免疫系统、生殖系统、骨骼系统、自分泌系统、消化和排泄系统、组胺系统和中枢神经系统。 By a flow regulator 200 with the osmotic delivery system 300 to deliver active agents include but are not limited to the role of infectious diseases, chronic pain, diabetes, the peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, cardiovascular system , smooth muscles, blood circulatory system, synaptic location, nerve effector engaged position, endocrine and hormone system, immune system, reproductive system, skeletal system, autocrine system, digestive and excretory systems, the histamine system and the central nervous system. 适合的试剂可选自例如蛋白质、酶、 激素、多核苷酸、核蛋白、多糖、糖蛋白、脂蛋白、多肽、留体、镇痛药、局部麻醉药、抗生素、抗炎用皮质类固醇、眼用药物和这些物质的合成类似物。 Suitable agents may be selected from, for example proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroidal, analgesics, local anesthetics, antibiotics, anti-inflammatory corticosteroids, ocular with drugs and synthetic analogs of these species. 优选的活性剂包括大分子(蛋白质和肽)和高度有效的活性剂。 Preferred active agents include macromolecules (proteins and peptides) and active agents highly effective. 活性剂可以作为多种化学和物理形式存在,例如固体、液体和浆状物。 Active agents can be used as a variety of chemical and physical forms, such as solid, liquid, and slurry. 除了一种或多种活性剂之外,制剂320可以任选地包括药学可接受的载体和/或另外的成分,例如抗氧化剂、稳定剂、缓冲剂和渗透增强剂。 In addition to the one or more active agents, the formulation 320 may optionally include pharmaceutically acceptable carriers and / or additional ingredients such as antioxidants, stabilizers, buffers, and permeation enhancers.

[0051] 用于容器302的材料应该充分坚硬,以便经得起渗透动力物质318的膨胀而不改变其大小或形状。 Materials [0051] 302 for the container should be sufficiently rigid to withstand expansion osmotic engine 318 without changing its size or shape. 此外,所述材料应该保证容器302不会在植入过程中所受到的应力下或由于操作过程中产生的压力的应力下渗漏、裂缝、破裂、或变形。 Furthermore, the material should ensure that the pressure will not stress the container 302 is subjected during implantation or during operation due to the stress generated in the leak, crack, fracture, or deformation. 容器302可由本领域已知的惰性的、生物相容的、天然的或合成的材料形成。 Container 302 may be known in the art inert, biocompatible, natural or synthetic material. 容器302的材料可以是或者不是生物可侵蚀的。 The material of the container 302 may or may not bioerodible. 生物可侵蚀的材料在其应用的流体环境中至少部分溶解、降解、或者以其它方式腐蚀。 Bioerodible material at least partially dissolved in the fluid environment of its application, the degradation, corrosion, or otherwise. 优选地,容器302的材料不是生物可侵蚀的。 Preferably, the container material 302 is not bioerodible. 通常,优选的容器302的材料是适用于人类植入的那些。 Typically, the material of the container 302 is preferably applied to those human implantation. 优选地,容器302的材料是非渗透性的,特别是在容器302内的制剂稳定性对应用的流体环境敏感时。 Preferably, the material is impermeable container 302, in particular the stability of the formulation within the container 302 to the application when sensitive fluid environment. 适合于容器302的材料的实例包括非反应性聚合物或生物相容的金属或合金。 Materials suitable for container 302 include non-reactive metal or alloy or a biocompatible polymer. 用于容器302的非反应性聚合物的实例包括但不限于丙烯腈聚合物例如丙烯腈-丁二烯-苯乙烯三元共聚物;卤化的聚合物例如聚四氟乙烯、聚氯三氟乙烯、四氟乙烯和六氟丙烯共聚物;聚酰亚胺;聚砜;聚碳酸酯;聚乙烯;聚丙烯;聚氯乙烯-丙烯酸共聚物;聚碳酸酯-丙烯腈-丁二烯-苯乙烯;和聚苯乙烯。 Examples of non-reactive container 302 polymers include, but not limited to, acrylonitrile polymers e.g. acrylonitrile - butadiene - styrene terpolymer; halogenated polymers such as polytetrafluoroethylene, polychlorotrifluoroethylene , tetrafluoroethylene and hexafluoropropylene copolymers; polyimides; polysulfones; polycarbonate; polyethylene; polypropylene; polyvinyl chloride - acrylic acid copolymers; polycarbonate - acrylonitrile - butadiene - styrene ; and polystyrene. 容器的金属性材料的实例包括但不限于不锈钢、钛、钼、钽、金、和它们的合金,以及镀金的铁合金、镀钼的铁合金、钴铬合金和氮化钛涂层的不锈钢。 Examples of metallic materials include, but are not limited to containers of stainless steel, titanium, molybdenum, tantalum, gold, and their alloys, as well as gold-plated ferrous alloys, chrome molybdenum alloys, cobalt-chromium alloys and titanium nitride coated stainless steel. 对于尺寸决定性应用、高有效载荷能力、长持续时间应用、和其中制剂对植入位置的体内化学敏感的应用,优选容器302由钛、或具有大于60% (通常大于85% )钛的钛合金制成。 For critical dimension applications, high payload capability, long duration applications, and wherein the formulation for in vivo implantation site of the chemical sensitive applications, the container 302 is preferably made of titanium or a titanium alloy having greater than 60% (typically greater than 85%) of titanium production.

[0052] 可以对流动调节器200的直径进行选择,使得流动调节器200可以压配合到容器302的开口末端304中。 [0052] The diameter of the flow may be selected regulator 200, flow regulator 200 that may be press fit into the open end 304 of container 302. 还有可能在外壳202的外表面220和容器302的内表面310上包括特征例如螺纹,用于相对于容器302固定流动调节器200。 It may also include features such as container 302 with respect to the fixed flow regulator screw 200, 310 on the inner surface to the outer surface 220 of the housing 202 and the container 302.

[0053] 以下实施例用于说明本发明,不应将其看作是限制本发明,除非本文中另有说明。 [0053] The following examples serve to illustrate the present invention and should not be construed as limiting the invention unless otherwise indicated herein.

[0054] 图3中说明的包含用于治疗例如丙型肝炎的干扰素-ω (IFN-ω)的渗透递送系统用以下组件装配:(i)由植入级钛合金制成并且在其末端具有底切的容器,(ii)包括两个圆柱形片剂的渗透动力物质,每个片剂主要包括具有纤维素和聚维酮粘合剂的氯化钠盐, (iii)活塞,(iv)由聚氨酯制成并且具有与容器中的底切配合的保持凸纹的半渗透性塞, (ν)具有D形横截面的螺旋形内部流动通道的流动调节器,直径0. 25mm,螺旋长度为35mm, 和(vi)包括悬浮在非水媒介物中的IFN-ω的颗粒制剂的悬浮液制剂。 Comprising an interferon -ω (IFN-ω) for the treatment of hepatitis C, for example, the osmotic delivery system [0054] Figure 3 illustrates the assembly of the following components: (i) is made of implant grade titanium alloy and at its end a container having an undercut, (ii) osmotic engine including two cylindrical tablets, each tablet including primarily sodium chloride salt with cellulosic and povidone binders, (iii) piston, (iv ) made of polyurethane and having a mating undercut relief vessel is maintained semipermeable plug, (v) flow modulator having a D-shaped cross-section of the spiral internal flow channel, 25mm, the length of the coil diameter 0.5 of 35mm, and a suspension formulation (vi) a suspension comprising IFN-ω in a non-aqueous vehicles particle formulation.

[0055] 将上述几个渗透递送系统的容器填充150 μ L的悬浮液制剂。 [0055] The above-described container filled with several osmotic delivery systems 150 μ L of a suspension formulation. 将渗透递送系统的半渗透性塞末端置于充满磷酸盐缓冲液(PBQ的小玻璃管中,将渗透递送系统的流动调节器末端置于充满含水释放介质的小玻璃管中。将系统分别在5°C和30°C存储或保温。在特定的时间点,可以将释放介质除去并且更换新的溶液。使用反相高效液相色谱法(RP-HPLC) 对取样的释放介质分析活性剂含量。图4表示在6月内的IFN-ω体外累计释放。 The osmotic delivery system semipermeable plug end disposed filled with phosphate buffer (small glass tube of PBQ, the osmotic delivery system flow modulator disposed end filled with an aqueous release medium glass vial. The system, respectively 5 ° C and 30 ° C stored or incubated at a particular point in time, the release medium may be removed and replaced with a new solution. using reverse phase high performance liquid chromatography (RP-HPLC) analysis of samples of the release media surfactant content Figure 4 shows in vitro IFN-ω June cumulative release.

[0056] 本发明可提供以下优点。 [0056] The present invention can provide the following advantages. 两件式流动调节器使得流动调节器的设计具有灵活性并且允许流动调节器的可制造性。 Two-piece flow regulator so that the flow regulator design flexibility and allow flow regulator manufacturability. 外壳与容器不是整体的,并且使得能够在将流动调节器插入到容器中之前检查流动调节器的通道。 Container is not integral with the housing, and such that can be inserted into the container before checking the channel of the flow regulator the flow regulator. 两件式流动调节器使得在将流动调节器插入到容器中的过程中对通道的另外的机械力最小化。 Two additional-flow regulator such that a mechanical force to minimize the passage flow regulator is inserted into the process vessel. 两件式流动调节器允许在保持共用的外套管的同时通过改变内芯或流动嵌入物上的通道而优化流动通道尺寸的灵活性。 Two-flow regulator allows, while maintaining a common outer sleeve and the flexibility to optimize the size of the flow channel by changing the inner core or flow insert path on the object.

[0057] 尽管已经参考有限的实施方案描述了实施方案,但是本领域技术人员在了解本发明之后应该理解,可以设计其它实施方案而不脱离本文公开的本发明的范围。 [0057] While the embodiment has been described with reference to the limited embodiments of embodiments, those skilled in the art will appreciate that in the understanding of the present invention, other embodiments may be devised without departing from the scope of the invention disclosed herein. 因此,本发明的范围仅由随附的权利要求限制。 Accordingly, the scope of the invention is only restricted by the appended claims.

Claims (17)

  1. 1.用于活性剂制剂的可植入渗透递送系统,包括: 由不可渗透材料制成的容器;在容器中的包含渗透动力物质的第一室; 在容器中的包含活性剂制剂的第二室;设置在容器内并且可以在其中移动的隔离物,所述隔离物限定包含渗透动力物质的第一室和包含活性剂制剂的第二室;设置在容器的第一末端的、与第一室邻接的半渗透性塞;和设置在容器的第二末端的、与第二室邻接的流动调节器,所述流动调节器包括: 定位在渗透递送系统的容器的第二末端的开口中的外壳,所述外壳包括内表面; 插入到所述外壳中的内芯,所述内芯包括外表面;和在所述外壳的内表面和内芯的外表面之间限定的螺旋状流动通道,所述流动通道适合于从渗透递送系统的容器递送活性剂制剂。 1. The active agent formulation may be used in implantable osmotic delivery system, comprising: a container made of impermeable material; comprising a first osmotic engine compartment in the container; a formulation comprising an active agent in the second container chamber; and may be disposed within the container in which the movable spacer, said spacer defining the osmotic engine comprising a first chamber and a second chamber containing an active agent formulation; disposed at the first end of the container, with the first chamber adjacent to the semipermeable plug; and disposed at a second end of the container, a second chamber adjacent to the flow regulator, said flow regulator comprising: a second opening positioned at the end of the osmotic delivery system in a container a housing including an inner surface; an inner core inserted into said housing, said core including an outer surface; between the outer surface and the inner surface of the housing and the inner core defines a helical flow path, the flow channel is adapted to the container from the osmotic delivery system to deliver the active agent formulation.
  2. 2.权利要求1的可植入渗透递送系统,其中流动通道形成在与外壳的内表面配合的内芯的外表面上。 Claim 2. The implantable osmotic delivery system, wherein the flow channel is formed on the outer surface with the inner surface of the housing and the inner core.
  3. 3.权利要求1的可植入渗透递送系统,其中流动通道形成在与内芯的外表面配合的外壳的内表面上。 3. The implantable osmotic delivery system of claim, wherein the flow channel is formed on the inner surface mating with the outer surface of the inner core of the housing.
  4. 4.权利要求1的可植入渗透递送系统,另外包括设置在外壳和内芯之间的流动嵌入物,其中在所述流动嵌入物中形成流动通道。 The implantable osmotic delivery system further comprising a housing disposed between the inner core and the flow insert, wherein the flow channel is formed in the flow insert in the claim.
  5. 5.权利要求4的可植入渗透递送系统,其中外壳、内芯、和流动嵌入物由惰性材料形成。 According to claim 4 implantable osmotic delivery system, wherein the housing, the inner core, and flow insert is formed from an inert material.
  6. 6.权利要求5的可植入渗透递送系统,其中惰性材料是非金属材料。 According to claim 5 implantable osmotic delivery system, wherein the inert material is a non-metallic material.
  7. 7.权利要求1的可植入渗透递送系统,其中外壳和内芯由惰性材料形成。 The implantable osmotic delivery system, wherein the housing and the inner core is formed from inert material as claimed in claim 7.
  8. 8.权利要求7的可植入渗透递送系统,其中惰性材料是非金属材料。 Claim 7 implantable osmotic delivery system, wherein the inert material is a non-metallic material.
  9. 9.权利要求8的可植入渗透递送系统,其中所述材料是聚醚醚酮、聚芳醚醚酮、超高分子量聚乙烯、氟化的乙烯-丙烯、聚甲基戊烯或液晶聚合物。 9. The process according to claim 8 implantable osmotic delivery system, wherein said material is a polyether ether ketone, poly aryl ether ether ketone, ultra high molecular weight polyethylene, fluorinated ethylene - propylene, polymethylpentene, or liquid crystal polymer thereof.
  10. 10.权利要求1的可植入渗透递送系统,其中外壳密封啮合所述内芯。 10. The implantable osmotic delivery system of claim, wherein the housing seal engages the inner core.
  11. 11.权利要求1的可植入渗透递送系统,其中所述内芯包括外侧肩部,所述外壳包括内侧肩部,其中所述外侧肩部和内侧肩部啮合,以防止在使用中内芯从外壳排出。 11. The claim 1, an implantable osmotic delivery system, wherein the inner core includes an outer shoulder, the inner housing comprises a shoulder, wherein the outer shoulder and inner shoulder engage to prevent, in use, the inner core It is discharged from the housing.
  12. 12.权利要求1的可植入渗透递送系统,其中流动通道的长度为10到50mm。 Claim 12. The implantable osmotic delivery system, wherein the length of the flow channel is 10 to 50mm.
  13. 13.权利要求1的可植入渗透递送系统,其中流动通道的有效截面直径为0. 1到0. 5mm。 Claim 13. The implantable osmotic delivery system, wherein the effective cross-sectional diameter of the flow channel 0.1 to 0. 5mm.
  14. 14.权利要求1的可植入渗透递送系统,其中流动调节器被压配合到容器的第二末端中。 14. The implantable osmotic delivery system of claim, wherein the flow modulator is press-fitted into the second end of the container.
  15. 15.权利要求1-14任一项的可植入渗透递送系统,其中活性剂制剂选自干扰素-ω。 According to any of claims 1-14 15. The implantable osmotic delivery system, wherein the active agent formulation is selected from interferon -ω.
  16. 16.权利要求1-14任一项的可植入渗透递送系统,其中所述容器的材料选自钛或钛合金。 According to any of claims 1-14 16. The implantable osmotic delivery system, wherein the vessel material is selected from titanium or a titanium alloy.
  17. 17.权利要求1-14任一项的可植入渗透递送系统,其中所述隔离物为可滑动活塞。 17. The implantable claims 1-14 osmotic delivery system, wherein the spacer is a piston slidably.
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